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Journal of Journal of Parathyroid Disease 2017,5(1),25–27 Case Report

Long-term hypercalcemia due to parathyroid adenoma resulting in hypercalcemic crisis; an autopsy case report Biserka Pigac1, Silvija Mašić2*, Zdenka Hutinec3, Valentina Mašić4

Abstract We present a case of parathyroid adenoma resulting in hypercalcemic crisis with lethal outcome and subsequential autopsy findings pointing out to long term hypercalcemia. A 51- year-old female was admitted to hospital due to vomiting, constipation, general weakness, hypotension and uncorrectable . A couple of hours after the admission her general appearance deteriorated and she became disoriented, more pale and developed both eye blindness. Laboratory findings revealed leukocytosis, increased values of urea, hypokalemia, thrombocytopenia, high blood (26 mg/dL) pointing out to hypercalcemic crisis. Hypercalcemia was immediately treated, but unsuccessfully leading to lethal outcome. Autopsy revealed presence of pulmonary oedema, ascites, acute pancreatitis, diffuse of arteries, bone osteopenia, left pulmonary artery thromboembolism, heart hypertrophy and nodule under the right thyroid lobe which was later pathohistologically described as parathyroid adenoma. Presence of chronic hypercalcemia due to parathyroid adenoma is difficult to be recognized since most cases are asymptomatic, but it is necessary in order to avoid chronic complications of calcium deposition and possible development of hypercalcemic crisis which is life threatening condition demanding immediate treatment. Keywords: Parathyroid adenoma, Hypercalcemia, Hypercalcemic crisis, Pathology, Autopsy, Please cite this paper as: Pigac B, Mašić S, Hutinec Z, Mašić V. Long-term hypercalcemia due to parathyroid adenoma resulting in hypercalcemic crisis; an autopsy case report. J Parathyr Dis. 2017;5(1):25-27. Copyright © 2017 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction Urination was normal, without any pain or discomfort. Parathyroid adenoma is the most common cause of pri- Due to prostrated appearance of the patient, the physician mary hyperparathyroidism in approximately 85% of sent her to department for infectious diseases under the cases, gland hyperplasia and multiple adenomas in 15%, suspicion on acute gastroenterocolitis. During examina- parathyroid carcinoma in around 1% of cases (1). Hyper- tion by the infectologist findings were these: the patient parathyroidism is classified as primary, secondary which was afebrile, oriented, prostrated, dehydrated and hypo- means increase in levels due to hy- tensive (RR was 90/60). Auscultation of heart and lungs pocalcemia in conditions such as chronic renal failure, and revealed no abnormalities. Abdominal examination was then tertiary caused by chronic stimulation of parathyroid normal, lumbar areas were painless, no melena or rectal glands (2). Incidence of primary is 1 in 500 women and 1 bleeding were found. No rash was present on skin. Men- in 2000 men older than 40 years of age (3). Primary hyper- ingeal signs were negative. Laboratory findings demon- parathyroidism is usually asymptomatic and chronic but it strated leukocytosis (18.7×109/L), thrombocytopenia is believed that parathyroid adenomas can start to secrete (57×109/L), increased C-reactive protein (33 mg/L) with large amount of parathyroid hormone which results in ex- increased values of urea (20.86 mg/dl) and hypokalemia treme increase in calcium levels and hypercalcemic crisis (8.99 mg/dL). Urine analysis revealed increased number (4). Here we describe a case of a patient in hypercalcemic of leukocytes (30-40) and large amount of bacteria. The crisis with fatal outcome and emphasize the importance patient was kept for observation. During that time she of recognizing causes and presence of hypercalcemia in received infusion of 0.9% NaCl and KCl and antibiotic order to avoid negative consequences. therapy with cephalosporin was included. The patient was afebrile and no vomiting was observed during obser- Case Presentation vation. She was further sent and admitted to department A 51-year-old woman visited her family physician because of internal medicine for further analysis of hypokalemia of vomiting and general weakness that lasted for 4 days. and acute renal insufficiency. During admission the pa- No abdominal pain, nausea or increased body tempera- tient was still afebrile, oriented, prostrated, pale, eupnoic. ture were present. She had no stool for the past 4 days. Blood pressure was 120/75 mm Hg. The examination

Received: 15 May 2016, Accepted: 1 August 2016, ePublished: 23 August 2016 1Pathology, Cytology and Forensic Medicine Unit, Varaždin General Hospital,Varaždin, Croatia. 2Educational Institute of Emergency Medicine of City of Zagreb, Zagreb, Croatia. 3Department of Pathology, University Hospital Centre Zagreb, Zagreb, Croatia. 4Training and Education Center ‘Vinko Bek’, Zagreb, Croatia. *Corresponding author: Silvija Mašić, Email; [email protected] Pigac B et al

Implication for health policy/practice/research/ roid gland under the right lobe, nodule 4 cm in its longest medical education diameter was noticed which was later pathohistological- This case is important for practitioners since it implicates the ly examined and characterized as parathyroid adenoma. significance of recognizing disorder of calcium levels which Further, fibrosis of myocardial muscle was found with hy- often remains undiagnosed due to lack of symptoms and can pertrophy of all heart chambers, especially left ventricle. lead to life threatening conditions such as hypercalcemic Lungs were filled with fluid characterized as pulmonary crisis. It educates practitioners on symptoms of hypercalcemia oedema. Also, thromboembolism of the left pulmonary and hypercalcemic crisis and points out to possible causes of artery was observed. Abdominal cavity was filled with 200 this disorder focusing on parathyroid adenoma as the most mL of thick, blood-tinged ascites. Liver was regularly sized common cause of primary hyperparathyroidism. but with fatty changes. Pancreas demonstrated inflamma- tory changes meaning acute hemorrhagic pancreatitis. of lungs, heart, abdomen, lumbar area and rectum was Both kidneys were filled with cysts. Arteries demonstrated normal. EKG demonstrated normal sinus rhythm with atherosclerotic changes with extreme calcification of ves- frequency of 90 beats/min, first degree atrioventricular sel walls. Osteopenia due to long term hypercalcemia was block and S-T denivelation. The patient complained only visible on all bones, especially on bones of the skull which on pain in her knees. Her anamnestic data have so far re- were extremely thin (as paper) and were able to be cut by vealed long term knee pain and renal colics 7 years before using regular scissors. this admission. She demonstrated so far no allergies. Few Pathological examination was performed on removed hours after the admission the patient became more pros- tissue. It was solitary tan nodule 4 cm in its longest di- trated, extremely pale, disoriented and hypotensive. In ameter well circumscribed from the surrounding tissue. addition, she complained on blindness on both eyes. Neu- Routine hemalaun & eosin staining revealed encapsulat- rologist was consulted and suggested head CT-scan. Labo- ed lesion consisted of unimorphous small cells arranged ratory examination was repeated and showed leukocytosis in nests (Figure 1). No capsular or invasion to adjacent (21.5× 109/L), increased values of urea (21.7 mg/dL), hy- tissues were noticed. Immunohistochemical staining for pokalemia (12.12 mg/dL), thrombocytopenia (20×109/L), parathyroid hormone revealed strong positivity for this values of amylases in both blood (89 IU/L) and urine (142 marker suggesting the diagnosis of parathyroid adenoma IU/L) were under reference range. Creatine kinase was (Figure 2). increased (490 IU/L). Also, liver enzymes demonstrated increased values: lactate dehydrogenase (341 IU/L), alka- Discussion line phosphatase (139 IU/L), aspartate aminotransferase In our case, cause of patient’s symptoms was parathyroid (42 IU/L). C- reactive protein was increased (52 mg/L). adenoma and after immunohistochemical positivity for Blood calcium was increased (26 mg/dl), phosphorus was parathyroid hormone we demonstrated that this benign 4.49 mg/dl. According to symptoms and values of calcium tumor secreted this hormone, led to long term hypercal- that pointed out to hypercalcemic crisis the patient was cemia (we concluded based on autopsy findings such as immediately treated with pamidronate, furosemide, glu- bone osteopenia, artery , but also on anam- cocorticoids and intravenous infusions of 0.9% NaCl. De- nestic data of renal colics probably due to renal stones and spite the therapy, the patient’s condition deteriorated and knee pain) and finally led to extreme increase in calcium she developed ventricular tachycardia with subsequential levels meaning hypercalcemic crisis. cardiorespiratory arrest. Cardiopulmonary resuscitation Normal levels of total calcium are 8.82-10.42 mg/dL, nor- was performed but without success. Lethal outcome was mal values of ionized calcium are 4.4-5.6 mg/dL (3). Pa- recorded on second day after the admission. tients with calcium levels of 10.42-12.02 mg/dL usually Autopsy was performed 56 hours after patient’s death. demonstrate no symptoms, but above those serum calci- Results of the examination demonstrated cyanosis of the um levels, clinical manifestation appear involving multi- entire body skin. In the area of the neck, below the thy- ple organs (3). In most patients with hyperparathyroid-

Figure 1. Parathyroid adenoma consisted of unimorphous small Figure 2. Strong positivity of parathyroid adenoma cells on cells arranged in nests (H&E, 60×). parathyroid hormone (PTH, 60×).

26 Journal of Parathyroid Disease, Volume 5, Issue 1, March 2017 Parathyroid adenoma resulting in hypercalcemic crisis ism, symptoms of hypercalcemia are not apparent which is necessary for adequate patient treatment and avoidance makes determination of the correct diagnosis difficult. of lethal outcome. Also, recognition of chronic hypercal- When recognized and treated in time the disease can be cemia due to parathyroid adenoma presence is difficult adequately resolved (3). Chronic hypercalcemia in case to be recognized since most cases are asymptomatic, but of parathyroid adenoma can present with symptoms like it is necessary in order to avoid chronic complications of weakness, fatigue, anorexia, nausea, vomiting, polydipsia, calcium deposition and possible development of hypercal- polyuria, weight loss, constipation, headaches, musculo- cemic crisis. skeletal pain and disorders, pathological fractures, renal Authors’ contribution stones, pancreatitis, anemia, peptic ulcer (5). Hyper- BP; acquisition and analysis of data, critical revision of the calcemic crisis in primary hyperparathyroidism is rare manuscript. SM; acquisition of data, design, drafting and condition, but medical emergency and life threatening critical revision of the manuscript. ZH; analysis of data, condition which requires early recognition, immediate critical revision of the manuscript. VM; drafting and crit- treatment of hypercalcemia and early parathyroidectomy ical revision of the manuscript. as definite treatment to avoid patient’s adverse outcome (1,6,7). Its incidence is around 1.6%-6% (7) Calcium level Conflicts of interest above 3.5 mmol/L is treated as hypercalcemic crisis and The authors declared no competing interests. requires urgent treatment (8). It is considered that pa- Ethical considerations tients with chronic hypercalcemia in hyperparathyroid- Ethical issues (including plagiarism, data fabrication, ism, like in our case, can develop hypercalcemic crisis in double publication) have been completely observed by the case precipitating causes like trauma, surgery or infec- authors. tion occur (9). Prompt treatment of hypercalcemic crisis is necessary since critical levels of calcium lead to organ Funding/Support failure (7). Symptoms include gastrointestinal symptoms, None. dehydration, renal damage, deterioration of mental status, References multiple organ failure and possible death (5,7). Blindness 1. Brown TC, Healy JM, McDonald MJ, Hansson JH, that the patient developed can be explained as neurocog- Quinn CE. Heart block and acute kidney injury due to nitive symptom of hypercalcemic crisis. Neurocognitive hyperparathyroidism-induced hypercalcemic crisis. Yale J symptoms appear due to hypercalcemia induced change Biol Med. 2014;87:563-7. of neurotransmitters (1). We have so far found no pa- 2. Dogan U, Koc U, Mayir B, Habibi M, Dogan B, Gomceli I, et pers describing blindness in hypercalcemic crisis. It also al. Life-threatening intrathyroidal parathyroid adenoma. Int leads to appearance of cardiac arrhythmias such as Q-T J Clin Exp Med. 2015;8:1501-3. 3. Ameerudden S, He X. Management and surgical treatment shortening, ventricular tachycardia, ventricular fibrilla- of parathyroid crisis secondary to parathyroid tumors: tion, atrioventricular block (1). We believe that our pa- report of four cases. Int Med Case Rep J. 2011;4:59-66. tient suffered chronic hypercalcemia since calcifications 4. Huang SC, Wu VC, Chou G, Huang TY, Lin SY, Sheu WH. were present. They led to destruction of blood vessels Benign parathyroid adenoma presenting with unusual and organ damage. Finally, pulmonary oedema occurred parathyroid crisis, anemia and myelofibrosis. J Formos Med due to destruction of alveolar/capillary barrier (10). As Assoc. 2007;106:13-6. differential diagnosis of hypercalcemia these causes can 5. Mishra A, Newman D. An interesting case of life-threatening be considered: hyperparathyroidism, intoxica- hypercalcemia secondary to atypical parathyroid adenoma tion, malignant tumors (parathyroid carcinoma, multiple versus parathyroid carcinoma. Case Rep Med. 2014; 2014:473814. myeloma, breast cancer, lung, renal carcinoma, head and 6. Sumana BS, Sabaretnam M, Sarathi V, Savith A. Functional neck malignancy), medications (lithium, thiazide diuret- parathyroid cystic adenoma: A rare cause of hypercalcemic ics), endocrine disorders (adrenal insufficiency), genetic crisis with primary hyperparathyroidism. Indian J Pathol disorders (familial hypocalciuric hypercalcemia) and oth- Microbiol. 2015;58:487-90. er causes (immobilization, Paget’s disease) (11). Diagnosis 7. Singh DN, Gupta SK, Kumari N, Krishnani N, Chand G, is determined through anamnestic data, clinical examina- Mishra A, et al. Primary hyperparathyroidism presenting tion, total and ionized serum calcium, electrolytes, urea, as hypercalcemic crisis: Twenty-year experience. Indian J creatinine, phosphate, x-ray of lungs, ultrasound (12). Endocrinol Metab. 2015;19:100-5. Treatment for hypercalcemia includes saline hydration, 8. Loh HH, Noor NM. The use of hemodialysis in refractory hypercalcemia secondary to parathyroid carcinoma. Case diuretics, bisphosphonates, steroids, calcitonin and hae- Rep Crit Care. 2014;2014:140906. modialysis in case of hypercalcemia refractory for stan- 9. Kuan YC, Tan F. Hypercalcemic crisis – a fatal case of primary dard treatments (3,8). Parathyroidectomy is considered to hyperparathyroidism. Med J Malaysia. 2014;69:231-3. be the most effective therapy for primary hyperparathy- 10. Liou JH, Cho LC, Kaohsiung YHH. Paraneoplastic hyper- roidism (3). calcemia with metastatic calcification – clinicopathologic studies. Kaohsiung J Med Sci. 2006;22:85-8. Conclusion 11. Schade DS. A Practical Approach to Hypercalcemia. Am To conclude, early recognition of hypercalcemic crisis and Fam Physician. 2003; 67:1959-66. prompt lowering of calcium with recognition of the cause 12. Ivančević Ž. MSD priručnik dijagnostike i terapije.Split: Placebo; 2010. p. 2990.

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